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US20030064082A1 - Antipsychotic agents stimulate neurogenesis in brain - Google Patents

Antipsychotic agents stimulate neurogenesis in brain Download PDF

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US20030064082A1
US20030064082A1 US10/262,996 US26299602A US2003064082A1 US 20030064082 A1 US20030064082 A1 US 20030064082A1 US 26299602 A US26299602 A US 26299602A US 2003064082 A1 US2003064082 A1 US 2003064082A1
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increase
brain
neurogenesis
individual
neurons
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Fung-Chow Chiu
Sahebarao Mahadik
Chandramohan Wakade
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Augusta University Research Institute Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to prevention and treatment of neurodegeneration and disease of the brain. More particularly, the present invention relates to the use of atypical neuroleptics to stimulate neurogenesis in adult brain.
  • Schizophrenia is considered to be, at least in part, a neurodegenerative and neurodevelopmental disease. Progressive ventricular dilation has been reported in 30 to 50% of schizophrenics (Johnstone et al., Lancet, 11 , 924 - 926 , 1996 ; Garver, Harvard Rev. Psychiatry, 4, 1-11, 1997; Davis et al., Biol. Psych., 43, 783-793, 1998; Lieberman, J Clin. Psychiatry, 60 (Suppl. 12), 9-12, 1999). In addition, a progressive deficit in cognition is a hallmark of schizophrenia.
  • Parkinson's disease is associated with a loss of dopaminergic neurons in certain brain regions.
  • Alzheimer's Disease is characterized by the death of nerve cells in regions of the brain involved in language and memory.
  • aging appears to be associated with a decrease in synapse plasticity which thereby leads to a reduction in memory.
  • other neurodegenerative diseases include Huntington's chorea and amyotrophic lateral sclerosis (Lou Gehrig's disease).
  • the treatment will allow for controlled neurogenesis to replace damaged neurons, or to prevent the loss of neurons.
  • the treatment will employ a compound that has few side effects.
  • compounds that prevent or reduce neurodegeneration may be used to prevent a variety of diseases, or may be used to specifically target one disease or brain region.
  • the present invention describes the use of antipsychotic agents, such as atypical neuroleptics, to stimulate neurogenesis in adult brain.
  • antipsychotic agents such as atypical neuroleptics
  • the present invention provides methods and compositions to treat neurodegenerative diseases by increasing the number of newly dividing cells that may be recruited to replace dead neurons in regions of the brain affected by such diseases.
  • the present invention may be used to replace neurons lost from natural causes such as aging, to thereby improve cognition, processing of sensory stimuli (e.g. olfactory stimulation), and other brain functions.
  • the present invention comprises a method to increase neural cell replacement and repair in the brain of an individual comprising administering an antipsychotic agent to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • the present invention comprises a method to increase the generation of new neurons in the brain of an individual comprising administering at least one atypical neuroleptic to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • the present invention comprises a composition to increase the generation of new neurons in the brain of an individual comprising at least one atypical neuroleptic, wherein said atypical neuroleptic is present in such an amount as to increase neurogenesis by a predetermined amount in at least one region of the individual's brain.
  • the present invention also comprises a method to treat symptoms associated with loss of brain function in an individual comprising administering at least one atypical neuroleptic to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain and thereby ameliorate the symptoms associated with loss of brain function.
  • the present invention comprises a kit to increase the generation of new neurons in the brain of an individual comprising a pharmacologically effective amount of an atypical neuroleptic packaged in a sterile container and instructions for application of the atypical neuroleptic to an individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • an object of the present invention is to provide methods and compositions for increasing neuronal regeneration and repair in adult brain.
  • an object of the present invention is to treat symptoms associated with loss of brain function.
  • FIG. 1 illustrates immunochemical staining for BrdU uptake in the subventricular zone (SVZ) of rats treated with (A) vehicle (drinking water); (B) Haloperidol (haldol); (C) Risperidone; and (D) Olanzapine, in accordance with an embodiment of the present invention.
  • FIG. 2 illustrates double immunofluorescent staining for BrdU uptake and proliferating cell nuclear antigen (PCNA) in cells of the subventricular zone in accordance with an embodiment of the present invention.
  • FIG. 4 illustrates double immunofluorescent staining of the subventricular zone for (A) BrdU and the neuronal specific antigen NeuN or (B) BrdU and the glia specific antigen glial fibrillary acidic protein (GFAP) in accordance with an embodiment of the present invention.
  • the region labeled (V) corresponds to the ventricle and the region labeled S corresponds to the striatum.
  • Arrows in A show some of the BrdU+/NeuN+ cells.
  • the present invention describes the use of antipsychotic agents, such as atypical neuroleptics to stimulate neuronal cell regeneration and repair in adult brain.
  • antipsychotic agents such as atypical neuroleptics to stimulate neuronal cell regeneration and repair in adult brain.
  • the present invention provides methods and compositions to treat neurodegenerative diseases by increasing the number of newly dividing cells that may be recruited to replace dead neurons in regions of the brain affected by such diseases.
  • the present invention may be used to replace neurons lost from natural causes such as aging and to improve cognition.
  • antipsychotic agents comprise a functional category of neuroleptic drugs used in the treatment of psychosis and that are able to ameliorate thought disorders.
  • atypical neuroleptics are compounds that are antipsychotic agents with extra-dopaminergic activities.
  • Atypical neuroleptics include, but are not limited to, Olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine), Risperidone (3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one) and Clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine).
  • typical neuroleptics are compounds that are antipsychotic agents with only dopaminergic activities.
  • Typical neuroleptics include, but are not limited to, Haloperidol, also known as haldol.
  • bromodeoxyuridine comprises 5-bromo-2′-deoxyuridine, a thymidine analog that is incorporated into DNA during cell division.
  • neurogenesis comprises cell division and differentiation of cells from an ectoderm origin to nervous system tissue.
  • neurogenesis includes any process by which neurons and glial cells are generated from precursor cells.
  • neurodegeneration comprises the loss of nerve cells or neuronal function. Neurodegeneration is often incremental and progressive.
  • neurons comprise any of the conducting cells of the nervous system.
  • neurons typically include a cell body, several short radiating processes (dendrites) that receive signals and one long process (axon) that sends signals.
  • glia comprise the supportive tissue of the brain; these cells do not conduct electrical impulses.
  • astrocytes There are three types of glia: astrocytes, oligodendrocytes, and microglia.
  • cognition describes the ability of the brain to process information in such a manner as to allow the individual to use or learn from the information including, but not limited to, the mental processes of knowing, thinking, learning, and judging.
  • the subventricular zone lines the ventricles is the cell layer ventral and lateral to the ependymal layer.
  • the subventricular zone consists of immature cells and precursor cells that arc capable of cell division, but that are not functional as neurons or glia.
  • the hippocampus comprises an area of the brain important for long term memory and is a site of long-term synaptic plasticity.
  • Diseases which may comprise hippocampal involvement include schizophrenia, epilepsy and memory disorders.
  • schizophrenia is a heterogeneous group of mental disorders comprising most major psychotic disorders that are characterized by disturbances in form and content of thought, mood, sense of self, and relationship to the external world.
  • Alzheimer's disease is a progressive, neurodegenerative disease characterized by a loss of function and death of nerve cells in several areas of the brain leading to loss of cognitive function such as memory and language. Although the cause is not known, the disease is characterized by the appearance of unusual helical protein filaments in the nerve cells (neurofibrillary tangles) and by degeneration in cortical regions of brain, especially in the frontal and temporal lobes.
  • Parkinson's disease is a progressive, neurological disease that appears to be associated with changes in melanin-containing nerve cells in the brainstem (substantia nigra, locus coeruleus) with varying degrees of nerve cell loss and reactive gliosis along with eosinophilic intracytoplasmic inclusions (Lewy bodies), and below normal levels of dopamine in the caudate nucleus and putamen.
  • ADD Attention Deficit Disorder
  • the present invention describes methods and compounds to stimulate neuronal replacement and repair in adult brain.
  • the present invention describes that compounds that are known to have anti-psychotic effects and that are known to improve cognition may act by increasing the pool of new neurons in the brain.
  • the compounds that increase neurogenesis comprise atypical neuroleptics.
  • the present invention comprises a method to increase neural cell replacement and repair in the brain of an individual comprising administering an antipsychotic agent to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • the compound comprises at least one atypical neuroleptic.
  • the region of increased neurogenesis comprises the subventricular zone.
  • the region of increased neurogenesis comprises the hippocampus.
  • the increased neurogenesis is associated with migration of newly divided neurons within the brain.
  • the present invention utilizes the discovery that atypical neuroleptics increase neurogenesis in adult brain.
  • the present invention comprises a method to increase the generation of new neurons in the brain of an individual comprising administering at least one atypical neuroleptic to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • the increase in neurogenesis by a predetermined amount comprises generation of new neurons.
  • the region of increased neurogenesis comprises the subventricular zone (SVZ).
  • the predetermined amount of increased neurogenesis in the SVZ comprises at least a measurable increase. More preferably, the predetermined amount of increased neurogenesis in the SVZ comprises at least a 10% increase. More preferably, the predetermined amount of increased neurogenesis in the SVZ comprises at least a 20% increase. More preferably, the predetermined amount of increased neurogenesis in the SVZ comprises at least a 50% increase. More preferably, the predetermined amount of increased neurogenesis in the SVZ comprises at least a 100% (2-fold) increase. Even more preferably, the predetermined amount of increased neurogenesis in the SVZ comprises at least a 3-fold increase.
  • the region of increased neurogenesis comprises the hippocampus.
  • the predetermined amount of increased neurogenesis in the hippocampus comprises at least a measurable increase. More preferably, the predetermined amount of increased neurogenesis in the hippocampus comprises at least a 10% increase. More preferably, the predetermined amount of increased neurogenesis in the hippocampus comprises at least a 20% increase. More preferably, the predetermined amount of increased neurogenesis in the hippocampus comprises at least a 50% increase. Even more preferably, the predetermined amount of increased neurogenesis in the hippocampus comprises at least a 100% (2-fold) increase.
  • the increased neurogenesis is associated with migration of newly divided neurons within the brain.
  • the newly divided neurons migrate to regions of the brain comprising the corpus callosum, striatum, cortex, septum, basal ganglion or nucleus basalis.
  • the newly divided neurons replace damaged cells.
  • the increase in neurogenesis reduces or prevents symptoms associated with neurodegeneration. Also preferably, the increase in neurogenesis is associated with an improvement in the individual's cognition.
  • the increase in neurogenesis is associated with a reduction of symptoms associated with loss of brain function.
  • the individual has symptoms associated with schizophrenia.
  • the individual may have symptoms associated with Alzheimer's disease.
  • the method may also be used to ameliorate symptoms associated with Parkinson's disease or alternatively, Attention Deficit Disorder (ADD).
  • ADD Attention Deficit Disorder
  • the increase in neurogenesis is associated with a reduction of symptoms associated with stroke.
  • the neurogenesis-promoting compound may be administered as one dose or as a long-term treatment. Appropriate doses will depend on the exact compound used, the method of administration, and the medical needs of the patient.
  • the dose comprises administration of from 0.01 to 20 mg/kg/day. More preferably, the atypical neuroleptic comprises administration of a dose of from 0.05 to 5 mg/kg/day. Even more preferably, the atypical neuroleptic comprises administration of a dose of from 0.2 to 0.5 mg/kg/day.
  • an atypical neuroleptic is administered orally.
  • an atypical neuroleptic may be administered intravenously or intramuscularly.
  • the present invention describes the use of compounds to stimulate neurogenesis in adult brain.
  • the compounds used to stimulate neurogenesis comprise atypical neuroleptices.
  • typical neuroleptics such as haloperidol.
  • a new class of antipsychotic drugs are the atypical neuroleptics, such as Risperidone and Olanzapine. These drugs have been shown to be effective in treating schizophrenia with minimal extrapyramidal side effects.
  • Atypical neuroleptics appear to be able to modify various neuronal pathways.
  • Aytpical neuroleptics have both anti-dopaminergic (D2, D4) and anti-serotonergic (5HT-2A) effects, as well as a putative antidepressant activity (Ghaemi et al., Bipolar Disord., 2, 196-199, 2000; Glick et al., J. Psych. Res., 35, 187-191, 2001).
  • Olanzapine an atypical neuroleptic, induces the expression of superoxide dismutase and nerve growth factor (NGF)-receptor in vitro, and Clozapine increases fibroblast growth factor-2 expression in vivo (Li et al., J Neurosci. Res., 56, 72-75, 1999; Riva et al., Neuropharmacology, 38, 1075-1082, 1999).
  • NGF nerve growth factor
  • the present invention comprises a method to increase neural cell replacement and repair in an individual comprising administering at least one atypical neuroleptic to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • Effective atypical neuroleptics include Olanzapin, Risperidone, or Clozapine, although other atypical neuroleptics are within the scope of the present invention.
  • the cells that display increased neurogenesis are, or are destined to become, neurons.
  • the atypical neuroleptics preferably increase the presence of newly dividing neurons in a least one region of the brain.
  • cells which display increased neurogenesis include cells of the hippocampus and subventricular (subependymal) zone although other regions of the brain may comprise newly divided neurons as well.
  • treatment of rats with atypical neuroleptics for varying time periods up to, and including, 42 days show increased neurogenesis in specific regions of the brain.
  • a 21 day subchronic treatment period corresponds to about 3 years of treatment in human patients.
  • the increase in neurogenesis may be quantified as an increase in the uptake of bromodeoxyuridine (BrdU), a thymidine analogue that is incorporated into DNA during cell division, in neuronal cells.
  • Brain cells may be characterized as being either neurons or glia based on the presence of cell proteins typical of each cell type.
  • neuronal cells are characterized by the presence of NeuN, a neuronal cell protein, and glial (astrocyte) cells are characterized by the presence of glial fibrillary acidic protein (GFAP).
  • GFAP glial fibrillary acidic protein
  • FIG. 1 showing immunostaining of individual animals for BrdU, it can be seen that treatment of animals with atypical neuroleptics (panels C and D) leads to increased BrdU labeling of cells in the subventricular region as compared to controls (panel A), or animals treated with the typical neuroleptic, Haloperidol (panel B).
  • BrdU uptake is associated with the presence of another marker typical of cell division, proliferating cell nuclear antigen (PCNA) (FIG. 2).
  • PCNA proliferating cell nuclear antigen
  • the increase in cell division seen with atypical neuroleptics is quantified.
  • FIG. 3 shows results quantifying BrdU uptake in animals treated with the atypical neuroleptics Risperidone (R) and Olanzapine (O), as compared to animals treated with Haldol (H) or control animals (C). Results from five animals are shown for each group. Both Risperidone and Olanzapine induce a significant increase in the number of BrdU-positive (BrdU+) cells in the subventricular zone.
  • the increase in cell division seen with atypical neuroleptics is quantified to a measurable amount.
  • the atypical neuroleptics stimulate at least a 10% increase, and more preferably at least a 20% increase, and more preferably, at least a 50% increase in new cell division. Even more preferably, the atypical neuroleptics stimulate at least a 100% (2-fold) increase in new cell division and even more preferably, the atypical neuroleptics stimulate at least a 3-fold increase in new cell division as quantified by BrdU+ cells.
  • SVZ subventricular zone
  • hyperplasia i.e. new cell generation
  • FIG. 1 the thickening appears more rostrally than caudally.
  • new cell generation for cells migrating toward the olfactory bulb.
  • olfaction is impaired in schizophrenia and other neurodegenerative diseases, such as Alzheimer's dementia.
  • atypical neuroleptics may be used to restore olfaction in patients.
  • treatment with atypical neuroleptics is associated with BrdU labeled cells (i.e. newly divided cells) in several regions of the brain.
  • this labeling is the result of new neuronal growth in these regions.
  • these labeled cells are the result of migration of newly divided neurons from one region of the brain to another, as the generation of new neurons in the adult brain is believed to be largely restricted to the subventricular zone (SVZ) lining the lateral ventricles, and the subgranular zone (SGZ) of the dentate gyrus.
  • SVZ subventricular zone
  • SGZ subgranular zone
  • newly divided neurons may migrate from the subventricular zone to the olfactory bulb, via the rostral migratory stream.
  • newly divided cells may migrate from the dentate gyrus of the hippocampus to nearby brain regions including the corpus collosum.
  • newly divided cells are seen in the septum.
  • treatment with atypical neuroleptics results in newly divided cells in the cortex or the striatum.
  • Other regions which may comprise newly divided neurons which have migrated from the SVZ or the SGZ comprise the basal ganglion or the nucleus basalis.
  • the subventricular zone comprises immature cells that may differentiate into either neurons or glia.
  • treatment with atypical neuroleptics increases proliferation of neurons, but not glia.
  • FIG. 4 treatment of animals with Olanzapine results in an increase in BrdU positive (BrdU+) cells that also stain for the neuronal marker NeuN (FIG. 4A).
  • BrdU+ cells are detected (arrows in FIG. 4B), essentially none of the BrdU+ cells stain for the glial specific marker, glial fibrillary acidic protein (GFAP) (FIG. 4B).
  • GFAP glial fibrillary acidic protein
  • treatment of animals with atypical neuroleptics increases neurogenesis in the hippocampus (FIGS. 5 and 6) by a measurable amount.
  • the increase in neurogenesis comprises at least a 5% increase, and more preferably, at least a 10% increase, and more preferably, at least a 20% increase, and more preferably, at least a 50% increase. Even more preferably, the increase in neurogenesis comprises at least a 100% increase.
  • most of the BrdU positive cells associated with atypical neuroleptics reside in the subgranular layer of the dentate gyrus, indicative of a neuronal destiny (FIG. 5).
  • many of the BrdU+ cells in the subgranular layer are still NeuN ⁇ , indicative that they have not yet differentiated into neurons.
  • neurogenesis in the hilar region a region comprising predominantly glia.
  • glia maintain the ability to proliferate throughout the individual's lifetime. Replication and repair of neurons, however, is much more restricted. Most mature neurons are highly differentiated and specialized. Thus, neurons generally do not retain the ability to divide and form daughter cells. In contrast, immature cells in the brain, notably those found in the subventricular zone and in hippocampus, retain the ability to divide and form new neurons. However, the number of immature cells is small relative to the whole population in the brain. As the brain has only limited capacity to generate new neurons, the use of atypical neuroleptics to stimulate new cell production with few side effects is of great potential for use in restoring neuronal deficit as a result of neurodegeneration.
  • Atypical neuroleptics modulate dopaminergic and serotonergic activities and it has been postulated that the ability of atypical neuroleptics to affect multiple receptors may cause the antipsychotic effect typical of these drugs.
  • atypical neuroleptics stimulate neurogenesis by a trophic mechanism.
  • atypical neuroleptics have antidepressant activity. It has been described that chronic antidepressant treatment may be associated with neurogenesis (Malberg et al., J. Neursci., 20, 9104-9110, 2000).
  • Olanzapine has been shown to stimulate expression of nerve growth factor in vitro (Li et al., J Neurosci. Res., 56, 72-75, 1999) and Clozapine has been shown to modulate FGF-2 expression in vivo (Riva et al., Neuropharmacology, 38, 1075-1082, 1999).
  • the present invention comprises a composition to increase the generation of new neurons and neural cell replacement in an individual comprising at least one atypical neuroleptic, wherein the neuroleptic is present in such an amount as to increase neurogenesis by a predetermined amount in at least one region of the individual's brain.
  • the present invention comprises a kit to increase the generation of new neurons and neural cell replacement in an individual comprising a pharmacologically effective amount of an atypical neuroleptic packaged in a sterile container and instructions for application of the atypical neuroleptic to an individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain.
  • the predetermined amount of increased neurogenesis comprises the generation of new neurons.
  • the increased neurogenesis reduces or prevents symptoms associated with neurodegeneration.
  • the increased neurogenesis is associated with improved cognition.
  • the region of increased neurogenesis comprises the subventricular zone (SVZ). In an embodiment, the region of increased neurogenesis comprises the hippocampus.
  • the increase in cell division seen with atypical neuroleptics is quantified to a measurable amount.
  • the atypical neuroleptics stimulate at least a 10% increase, and more preferably at least a 20% increase, and more preferably, at least a 50% increase in new cell division. Even more preferably, the atypical neuroleptics stimulate at least a 100% ( 2 -fold) increase in new cell division and even more preferably, the atypical neuroleptics stimulate at least a 3-fold increase in new cell division as quantified by BrdU+ cells.
  • the increased neurogenesis is associated with migration of newly divided neurons within the brain.
  • the newly divided neurons migrate to regions of the brain comprising the corpus callosum, striatum, cortex, septum, basal ganglion or nucleus basalis.
  • the atypical neuroleptic ameliorates symptoms associated with loss of brain function.
  • the composition is used to increase neurogenesis in an individual that has symptoms associated with schizophrenia.
  • the composition is used to increase neurogenesis in an individual that has symptoms associated with Alzheimer's disease.
  • the individual has symptoms associated with Parkinson's disease.
  • the individual has symptoms associated with Attention Deficit Disorder.
  • the individual may have symptoms associated with stroke.
  • the atypical neuroleptic may be administered as one dose or as a long-term treatment. Appropriate doses will depend on the method of administration and medical needs of the patient.
  • the atypical neuroleptic comprises a dose of from 0.01 to 20 mg/kg/day. More preferably, the atypical neuroleptic comprises a dose of from 0.05 to 5 mg/kg/day. Even more preferably, the atypical neuroleptic comprises a dose of from 0.2 to 0.5 mg/kg/day.
  • administration of the composition of the present invention is intravenous.
  • administration of the composition is intra-arterial.
  • administration of the composition of the present invention is intramuscular.
  • administration of the composition is oral or as an aerosol.
  • administration of the composition is sublingual.
  • administration of the composition is transrectal, as by a suppository or the like.
  • compositions can be prepared by procedures known in the art.
  • the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivates; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc,
  • the compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
  • the coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.
  • the present invention provides methods for treating neurodegenerative diseases by increasing newly dividing cells that may be recruited to replace dead neurons in regions of the brain affect by such diseases.
  • long-term treatment up to 90 days
  • atypical neuroleptics produces an improvement of cognition (Mahadik et al, Biol. Psychiatry, 49, 133S, 2001).
  • the present invention provides a method to treat symptoms associated with loss of brain function in an individual comprising administering an atypical neuroleptic to the individual in such a manner as to increase neurogenesis by a predetermined amount in at least one region of the brain, to thereby ameliorate the symptoms associated with loss of brain function.
  • the increase in neruogenesis ameliorates symptoms associated with loss of brain function.
  • the increase in neurogenesis ameliorates symptoms associated with neurodegeneration.
  • the increase in neurogenesis is associated with improved cognition.
  • the region of increased neurogenesis comprises the subventricular zone (SVZ). In an embodiment, the region of increased neurogenesis comprises the hippocampus.
  • the increase in cell division seen with atypical neuroleptics is quantified to a measurable amount.
  • the atypical neuroleptics stimulate at least a 10% , and more preferably at least a 20% and more preferably, at least a 50% increase in new cell division.
  • the atypical neuroleptics stimulate at least a 100% (2-fold) increase in new cell division and even more preferably, the atypical neuroleptics stimulate at least a 3-fold increase in new cell division as quantified by BrdU+ cells.
  • the increased neurogenesis is associated with migration of newly divided neurons within the brain.
  • the newly divided neurons migrate to regions of the brain comprising the corpus callosum, striatum, cortex, septum, basal ganglion and nucleus basalis.
  • the newly divided neurons replace damaged cells.
  • the method is used to ameliorate symptoms associated with schizophrenia.
  • the method is used to ameliorate symptoms associated with Alzheimer's disease.
  • the method is used to ameliorate symptoms associated with Parkinson's disease.
  • the method is used to ameliorate symptoms associated with Attention Deficit Disorder.
  • the method is used to ameliorate symptoms associated with stroke.
  • the compound may be administered as one dose or as a long-term treatment. Appropriate doses will depend on the nature of the compound, the method of administration and medical needs of the patient.
  • the amount of compound comprises a dose of from 0.01 to 20 mg/kg/day. More preferably, the atypical neuroleptic comprises a dose of from 0.05 to 5 mg/kg/day. Even more preferably, the atypical neuroleptic comprises a dose of from 0.2 to 0.5 mg/kg/day.
  • the compound is administered orally.
  • the compound may be administered intravenously or intramuscularly.
  • Alzheimer's disease involves degeneration of cholinergic neurons in the striatum and nucleus basalis, regions of the brain which are located near the subventricular zone (SVZ).
  • SVZ subventricular zone
  • Parkinson's disease is associated with affected cells in the basal ganglia that may be replenished by the newly dividing cells which are increased upon treatment with these agents.
  • newly formed cells migrate form the subventricular zone to the basal ganglion and establish new dopaminergic pathways.
  • the present invention comprises methods for treating memory loss associated with hippocampal dysfunction such as memory loss due to aging and/or Alzheimer's.
  • hippocampal dysfunction such as memory loss due to aging and/or Alzheimer's.
  • an increase in hippocampal neurons is associated with recovery of memory and cognition.
  • the present invention comprises methods for treating memory losses associated with hippocampal dysfunction and cognitive deficiencies in schizophrenia.
  • the present invention provides alternative methods to treat other neurodevelopmental disorders such Attention Deficit Disorder.
  • other neurodevelopmental disorders such Attention Deficit Disorder.
  • cells produced in the subventricular zone may migrate to the affected region.
  • these compounds may also be used to reverse deficits in olfaction seen in some patients suffering from neurodegenerative diseases such as schizophrenia.
  • Animal studies indicate that newly generated neurons from the anterior subventricular zone (SVZ) migrate via the rostral migratory stream (RMS) and replenish olfactory neurons. Any structural defect or degeneration in the anterior SVZ could reduce the normal turnover of olfactory neurons, thus contributing to olfactory defects.
  • SVZ anterior subventricular zone
  • RMS rostral migratory stream
  • the present invention also provides methods for treating stroke. It has been found that the injury to the brain caused by stroke resulting from middle artery occlusion (MCAO) results in the generation of new neuroblasts in the SVZ, and that these new neurons can migrate to the damaged striatal area (Arvidsson et al., Nature Medicine, 8, 963-970, 2002). The present invention provides methods and compositions to increase the generation of new neurons in the SVZ that will migrate to other brain regions to replace neurons damaged by ischemic injury.
  • MCAO middle artery occlusion
  • bromodeoxyuridine (BrdU, Sigma Chemical, St. Louis, Mo.), dissolved in distilled water, was injected intraperitonally in a volume of 0.3 ml or less per rat to deliver a dosage of 50 mg/kg, for the labeling of newly divided cells.
  • BrdU bromodeoxyuridine
  • rats were anesthetized under ketamine (100 mg/kg) and xylazine (0.6 mg/kg) anesthesia with saline cardiac perfusion.
  • Brains were removed quickly, placed in a brain matrix, cut into 5-mm blocks, cryoprotected in O.C.T. (Tissue-Tek) compound and frozen in isopentane in liquid nitrogen. Samples were stored at ⁇ 80° C. until immunostaining.
  • Coronal brain sections 10 ⁇ m-thick, were cut in a cryotome. Every fifth section was processed for immunohistochemistry with anti-BrdU antibody (Sigma Chemical). Sections were fixed in 4% paraformaldehyde and denatured in 2 N HCl for 30 min. Following incubation with primary antibody, sections were developed with avidin-biotin reagents using a biotinylated donkey anti-mouse-IgG antibody (Vector Labs., Burlingame, Calif.) and diaminobenzidine (DAB). Separate investigators performed sectioning, immunostaining, and counting of BrdU-positive cells in a double-blinded manner. To ensure consistency, one investigator who was unaware of treatment and staining protocols was responsible for counting BrdU-positive cells for the entire study.
  • biotinylated donkey anti-mouse-IgG antibody Vector Labs., Burlingame, Calif.
  • DAB diaminobenzidine
  • SVZ was identified as the cell layer ventral and lateral to the ependymal layer. Sections from different groups were matched by anatomical features so that comparable sections were analyzed. Cells along the lateral aspect of the subependymal region including the dorsolateral angle of the ventricle on both left and right hemispheres, and ventral to the corpus callosum were counted. The few BrdU-positive cells present outside this area were not counted. Five sections from each animal were counted and the average total BrdU positive cells calculated. To validate the BrdU staining of newly divided cells, an antibody against proliferating cell nuclear antigen (PCNA), from Sigma Chemical, was also used.
  • PCNA proliferating cell nuclear antigen
  • FIG. 1 Shown in FIG. 1 is the staining for: (A) a vehicle-treated control rat; (B) a Haloperidol-treated rat; (C) a Risperidone-treated rat; and (D) an Olanzapine-treated rat.
  • the arrows show some of the BrdU+ cells. It can be seen that there is a distinct increase in BrdU staining (i.e.
  • FIG. 2 shows another cell cycle-specific marker found in dividing cells, proliferating cell nuclear antigen (PCNA) (FIG. 2).
  • PCNA proliferating cell nuclear antigen
  • rats were treated with vehicle, a typical neuroleptic or an atypical neuroleptic (Olanzapine) for 21 day s.
  • a single injection of BrdU was given to each rat intraperitoneally at day 20.
  • Frozen sections from vehicle-treated control were incubated with sheep-anti BrdU antibody, and with a monoclonal mouse-anti PCNA antibody.
  • Secondary antibodies were a combination of Cy-3-conjugated anti-sheep and Cy-2-conjugated anti-mouse antibody.
  • a nested, repeated-measures analysis of variances was utilized to determine whether differences in the mean number of cell counts differed from vehicle control for the three drugs (Haldolperidol, Olanzapine, and Risperidone) in the subventricular zone.
  • ANOVA repeated-measures analysis of variance
  • the rat nested within the drug group was considered a random effect, and the drug group and slice of the brain were considered as fixed effects.
  • a Dunnett's test was used to determine whether the mean number of cells for each drug was different from vehicle control.
  • a Tukey multiple comparison test was used to examine all pairwise differences between the drugs as well. All statistical significance was assessed at an alpha level of 0.05.
  • Panel (A) shows a vehicle-treated rat
  • panel (B) shows a Riperidone treated rat
  • panel (C) shows an Olanzapine-treated rat.
  • the arrows show BrdU+ cells in the subgranular layer of dentate gyrus, suggesting a potential neuronal destiny (FIG. 5).
  • the few BrdU-positive cells detected did not express NeuN (or GFAP), indicating that few, if any, new neurons are produced in the control or haloperidol-treated hippocampus.
  • FIG. 6 shows the results for 5 rats treated with a vehicle (C), haloperidol, a typical neuroleptic (H), or the atypical neuroleptics, Risperidone (R) and Olanzapine (O).
  • C vehicle
  • H typical neuroleptic
  • R Risperidone
  • O Olanzapine
  • FIG. 7 shows double immunofluorescent staining of hippocampal dentate gyrus.
  • the animal was treated with Olanzapine for 21 day s and a single injection of BrdU given intraperitoneally at day 20.
  • Frozen sections were incubated with sheep-anti BrdU and mouse-anti NeuN antibodies.
  • Secondary antibodies were a combination of Cy-3-conjugated anti-sheep antibody and Cy-2-conjugated anti-mouse antibody.
  • Arrows show 3 BrdU+/NeuN ⁇ cells in the subgranular layer, suggesting that the new cells in the subgranular layer were not mature enough to express the neuronal phenotype-specific marker, NeuN.
  • the arrowhead shows a BrdU+/NeuN+ cell in the apical region of the granular cell layer.
  • BrdU+/NeuN+ cells were only found in the atypical neuroleptic-treated animals (FIG. 7). Moreover, a few of the BrdU+/NeuN+ cells were observed in the apical portion of the granular cell layer of the dentate gyrus, where neurons that are more developed reside (FIG. 7).
  • Atypical Neuroleptics Improve Cognition
  • the present invention describes the use of atypical neuroleptics for neuronal regeneration and repair.
  • the invention relies on the discovery that atypical neuroleptics enhance neuronal cell division (as measured by uptake of bromodeoxyuridine).
  • Treatment with atypical neuroleptics is associated with increased neuronal cell division in specific regions of the brain.
  • treatment with atypical neuroleptics results in migration of new neurons to various regions of the brain, thus providing a source of neurons to replenish dead or dying cells.

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